Influenza A, B, and C viruses are members of the Orthomyxoviridae, which is a family of enveloped viruses with segmented, single-stranded, negative-sense RNA genomes. They are classified by antigenic differences in their nucleoprotein (NP) and matrix protein (M1), which are present within the virions. Influenza A viruses are further classified into 18 hemagglutinin (HA) subtypes (H1-H18) and 11 neuraminidase (NA) subtypes (N1-N11) on the basis of the antigenicities of their HA and NA. Most subtypes can be found in their natural reservoir of wild aquatic birds, but they can also infect mammalian species, such as humans, pigs, and horses. Influenza A viruses cause annual epidemics in humans and occasional pandemics that spread on a global scale with severe consequences for human health. Influenza B viruses naturally infect humans, and occasionally seals, and cause more limited epidemics than Influenza A viruses in humans every few years. Influenza C viruses infect humans and pigs. Seroepidemiological studies suggest that influenza C virus has been globally distributed, although it is clinically benign in humans.
Influenza A virions possess a lipid envelope that is acquired from the apical plasma membrane of infected cells during the budding process. The virions released from infected cells are generally spherical, ranging from approximately 80-120 nm in diameter. On the other hand, budding virions on the surface of infected cells present as mostly elongated particles and occasionally filamentous particles of uniform diameter. These virions are covered with projections called spikes. A large number of two glycoproteins, HA and NA, and small amounts of an ion channel protein (M2) are inserted into the envelope. The two glycoproteins form the spikes on the viral surface. The HA spikes are rod-shaped, while the NA spikes are mushroom-shaped with a box-shaped head that is connected to the lipid membrane by a stalk. M1, a peripheral membrane protein, is one of the most abundant viral proteins in the virion. It binds to the lipid envelope and is thought to form a layer beneath it to maintain the spherical or filamentous structure of the virion. The viral genome is enclosed in a shell mainly composed of a layer of M1 protein, HA and NA spikes, and the lipid envelope.
The genomes of influenza A and B viruses consist of eight single-stranded negative-sense RNA segments, while that of influenza C virus consists of seven RNA segments. Each viral RNA (vRNA) segment forms a ribonucleoprotein (RNP) complex which creates a twisted rod-like structure that is folded back and coiled on itself. The RNPs, but not the genomic RNA alone, are transcriptionally active. In the RNP complexes, the vRNA is associated with NP and a heterotrimeric RNA-dependent RNA polymerase complex that is composed of basic polymerase protein 1 (PB1), basic polymerase protein 2 (PB2), and acidic polymerase protein (PA). PB1 forms the core structure of the heterotrimeric RNA polymerase complex. The N-terminal region of PB1 binds to the C-terminal region of PA, and C-terminal region of PB1 binds to the N-terminal region of PB2.
Unlike most negative-sense RNA viruses, transcription and replication of the influenza virus genome occurs in the nucleus of infected cells. After synthesis of the genomic RNAs and viral proteins, RNPs are synthesized in nucleus and exported to the cytoplasm mediated by two viral proteins, M1 and nuclear export protein (NEP/NS2), through a cellular chromosome region maintenance 1 (Crm1) protein-dependent pathway. The RNPs are intracellularly transported to the budding site (i.e., the lipid rafts on the apical plasma membrane of polarized cells, while the transmembrane HA, NA, and M2 proteins are conveyed to the cell surface by the standard exocytic pathway. The RNPs are presumed to interact with the M1 proteins and/or the cytoplasmic tails of HA, NA, and M2 at the plasma membrane, to be packaged into virus particles. Finally, all of the viral components assemble into progeny virions, leading to budding from the apical plasma membrane by membrane fission.